Pyrrolotriazine compounds and methods of inhibiting TAM kinases
Described herein are compounds, methods of making such compounds, pharmaceutical compositions, and medicaments comprising such compounds, and methods of using such compounds to treat cancer.
1. A compound of structural formula II:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is pyridin-3-yl, pyridin-4-yl, pyrazol-4-yl, cyclohexyl, or 8-azabicyclo[3.2.1]oct-2-ene-3-yl, wherein R 1 is optionally substituted with up to four independently selected substituents;
R 2 is cyclohexyl substituted with hydroxy and optionally substituted with one or two additional substituents independently selected from C 1 -C 4 alkyl and fluoro, or is 4,5,6,7-tetrahydro-1H-indazolyl optionally substituted with one to three substituents independently selected from C 1 -C 4 alkyl and fluoro; and
R 3 is —C 3 -C 8 alkyl, —(C 2 -C 6 alkylene)-O—(C 1 -C 6 alkyl), C 3 -C 6 cycloalkyl, or —(C 2 -C 6 alkylene)-C 3 -C 6 cycloalkyl, wherein R 3 is optionally substituted with 1-5 substituents independently selected from deuterium, halo, and —OH.
2. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R 1 is optionally substituted with up to four substituents independently selected from halo, hydroxy, -CN, -(C 1 -C 4 alkyl optionally substituted with one or more substituents selected from cyano, hydroxy and halo), -C(O)NH 2 , -COOH, -(C 0 -C 3 alkylene)-C(O)-(C 1 -C 4 alkyl), -(C 0 -C 3 alkylene)-C(O)-NH-(C 1 -C 4 alkyl), -(C 0 -C 3 alkylene)-C(O)-NH-S(O) 2 -(C 1 -C 4 alkyl), -(C 0 -C 3 alkylene)-C(O)-O-(C 1 -C 4 alkyl), -(C 0 -C 3 alkylene)-COOH, -(C 0 -C 4 alkylene)-S(O) 2 -(C 1 -C 3 alkyl), -(C 1 -C 3 alkylene)-O-(C 1 -C 4 alkyl), -S(O)(═NH)-(C 1 -C 4 alkyl), -S(O) 2 -NH-(C 1 -C 4 alkyl), -(cyclopropyl)-(cyano-substituted C 1 -C 3 alkyl), -(cyclopropyl)-C(O)-NH-(C 1 -C 4 alkyl), -(C 1 -C 3 alkylene)-C(O)-heterocyclyl, -C(O)-(C 0 -C 3 alkylene)-heterocyclyl, -(cyclopropyl)-C(O)-heterocyclyl, -(C 0 -C 4 alkylene)-heterocyclyl, -(C 0 -C 3 alkylene)-C(O)-NH-heterocyclyl, -(C 0 -C 4 alkylene)-aryl, and -(C 0 -C 4 alkylene)-heteroaryl, wherein the heterocyclyl or heteroaryl portion of the R 1 substituent is optionally further substituted.
3. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R 1 is 1-((1-oxetan-3-ylcarbonyl)azetidin-3-yl)pyrazol-4-yl, 1-(1-(1,1-dioxothiomorpholin-4-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl, 1-(1-(1-trifluoromethylcyclopropylcarbonyl)azetidin-3-yl)pyrazol-4-yl, 1-(1-(2,2,2-trifluoroethan-1-yl)azetidin-3-yl)pyrazol-4-yl, 1-(1-(2,2-dimethylmorpholin-4-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl, 1-(1-(2,6-dimethylmorpholin-4-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl, 1-(1-(2-oxa-6-azaspiro[3.3]heptan-6-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl, 1-(1-(2-oxa-6-azaspiro[3.4]octan-6-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl, 1-(1-(3,3,3-trifluoropropan -1-yl)azetidin-3-yl)pyrazol-4-yl, 1-(1-(8-oxa-3-azabicyclo[3.2.1]octan-3-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl, 1-(1-(azetidin-l-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl, 1-(1-(ethan-2-ylsulfonyl)-3-(cyanomethyl)azetidin-3-yl)pyrazol-4-yl, 1-(1-(hexahydro-1H -furo[3,4-c]pyrrol-5-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl, 1-(1-(isopropylaminocarbonyl)cyclopropyl)pyrazol-4-yl, 1-(1-(morpholin-4-ylcarbonyl)-1-methylethan-1-yl)pyrazol-4-yl, 1-(1-(morpholin-4-ylcarbonyl)cyclopropyl)pyrazol-4-yl, 1-(1-(pyrrolidin-1-ylcarbonyl)cyclopropyl)pyrazol-4-yl, 1-(1,1-dioxotetrahydro-2H-thiopyran-4-yl)pyrazol-4-yl, 1-(1,3-dimethylpyrazol-5-yl)pyrazol-4-yl, 1-(1-acetylazetidin-3-yl)pyrazol-4-yl, 1-(1-acetylpyrrolidin-3-yl)pyrazol-4-yl, 1-(1-cyanocyclopropylmethyl)pyrazol-4-yl, 1-(1H -pyrazol-4-ylmethyl)ppyrazol-4-yl, 1-(1-hydroxy-3-chloropropan-2-yl)pyrazol-4-yl, 1-(1-hydroxylcarbonyl-1-methylethan-1-yl)pyrazol-4-yl, 1-(1-methoxycarbonylazetidin-3-yl)pyrazol -4-yl, 1-(1-methyl-2(1H)-pyridinon-5-ylmethyl)pyrazol-4-yl, 1-(1-methyl-2-oxopyrrolidin-4-ylmethyl)pyrazol-4-yl, 1-(1-methylaminocarbonyl-1-methylethan-1-yl)pyrazol-4-yl, 1-(1-methylsulfonylazetidin-3-yl)pyrazol-4-yl, 1-(1-t-butoxycarbonylpyrrolidin-3-yl)pyrazol-4-yl, 1-(2-(1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl, 1-(2-(2-(2-hydroxypropan-2-yl)morpholin-4-ylcarbonyl)propan-2-yl)pyrazol-4-yl, 1-(2-(2,5-dioxa-8-azaspiro[3.5]nonan-8-ylcarbonyl)propan-2-yl)pyrazol-4-yl, 1-(2-(2-methyl-1,3,4-oxadiazol-5-yl)propan-2-yl)pyrazol -4-yl, 1-(2-(2-methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-5-ylcarbonyl)propan-2-yl)pyrazol-4-yl, 1-(2-(2-methyl-6,7-dihydrothiazolo[4,5-c]pyridin-5-ylcarbonyl)propan-2-yl)pyrazol-4-yl, 1-(2-(3,5-dimethylpiperazin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl, 1-(2-(3-hydroxy-3-methylazetidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl, 1-(2-(3-hydroxy-3-methylpiperidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl, 1-(2-(3-hydroxy-3-methylpyrrolidin-1-ylcarbonyl)propan -2-yl)pyrazol-4-yl, 1-(2-(3-hydroxypyrrolidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl, 1-(2-(4-cyano-4-methylpiperidin-1-ylcarbonyl)propan-2-yl)pyrazol-4yl, 1-(2-(4-hydroxy-4-methylpiperidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl, 1-(2-(4-methyloxazol-2-yl)propan-2-yl)pyrazol-4-yl, 1-(2-(4-methylpiperazin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl, 1-(2-(5-(morpholin-4-yl)-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl, 1-(2-(5-(tetrahydrofuran-2-yl) -1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl, 1-(2-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)propan -2-yl)pyrazol-4-yl, 1-(2-(5-difluoromethyl-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl, 1-(2-(5-isopropyl-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl, 1-(2-(5-methyl-1,3,4-thiadiazol-2-yl)propan-2-yl)pyrazol-4-yl, 1-(2-(5-methyloxazol-2-yl)propan-2-yl)pyrazol-4-yl, 1-(2-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)propan-2-yl)pyrazol-4-yl, 1-(2-(methyl)-2-(morpholin-4-yl)propan-3-yl)pyrazol-4-yl, 1-(2-(methyl)-3-(morpholin-4-yl)propan-2-yl)pyrazol-4-yl, 1-(2-(pyrrolidin-1-ylcarbonyl)propan-2-yl)pyrazol-4-yl, 1-(2-cyanoethyl)pyrazol-4-yl, 1-(2-hydroxy -2-methylpropan-1-yl)pyrazol-4-yl, 1-(2-methoxyethyl)pyrazol-4-yl, 1-(2-methyl-3-hydroxypropan-2-yl)pyrazol-4-yl, 1-(2-methylpropyl)pyrazol-4-yl, 1-(2-methylsulfonylethan-1-yl)pyrazol-4-yl, 1-(2-morpholin-4-ylethyl)pyrazol-4-yl, 1-(2-oxopyrrolidin-3-yl)pyrazol-4-yl, 1-(2-oxopyrrolidin-4-ylmethyl)pyrazol-4-yl, 1-(3-methyl-1,2,4-oxadiazol-5-ylmethyl)ppyrazol-4-yl, 1-(3-methylsulfonylphenylmethyl)pyrazol-4-yl, 1-(4-methylpiperazin-1-ylcarbonylmethylppyrazol-4-yl, 1-(4-methylsulfonylphenylmethyl)pyrazol-4-yl, 1-(5-methyl -1,2,4-oxadiazol-3-ylmethylppyrazol-4-yl, 1-(5-methyl-1,3,4-oxadiazol-2-ylmethylppyrazol-4-yl, 1-(5-methylpyrazin-2-ylmethyl)pyrazol-4-yl, 1-(5-oxopyrrolidin-2-ylmethylppyrazol-4-yl, 1-(6-hydroxyhexahydrofuro[3,2-b]furan-3-yl)pyrazol-4-yl, 1-(6-methylpyrazin-2-ylmethyl)pyrazol-4-yl, 1-(ethoxycarbonylmethyl)pyrazol-4-yl, 1-(hexahydrofuro[2,3-b]furan-3-yl)pyrazol-4-yl, 1-(hydroxycarbonylmethyl)pyrazol-4-yl, 1-(isopropylaminocarbonylmethyl)pyrazol-4-yl, 1-(isopropylcarbonylmethyl)pyrazol-4-yl, 1-(methylaminocarbonylmethyl)pyrazol-4-yl, 1-(methylsulfonylaminocarbonylmethylppyrazol-4-yl, 1-(methylsulfonylmethyl)pyrazol-4-yl, 1-(morpholin-4-ylcarbonylmethyl)pyrazol-4-yl, 1-(oxetan-2-ylmethyl)pyrazol-4-yl, 1-(oxetan-3-ylmethyl)pyrazol-4-yl, 1-(pyrazin-2-ylmethyl)pyrazol-4-yl, 1-(pyridazin-4-ylmethyl)pyrazol-4-yl, 1-(pyridin-3-ylmethylppyrazol-4-yl, 1-(pyrrolidin-l-ylcarbonylmethylppyrazol-4-yl, 1-(tetrahydrofuran-2-ylmethyl)pyrazol-4-yl, 1-(tetrahydrofuran-3-yl)pyrazol-4-yl, 1-(tetrahydrofuran-3-ylaminocarbonylmethylppyrazol-4-yl, 1-(tetrahydropyran-4-yl)pyrazol-4-yl, 1-(tetrahydropyran-4-ylmethyl)pyrazol-4-yl, 1,3-dimethylpyrazol-4-yl, 1-difluoromethylpyrazol -4-yl, 1H-pyrazol-4-yl, 1-methylpyrazol-3-yl, 1-methylpyrazol-4-yl, 1-oxetan-3-ylpyrazol-4-yl, 1-t-butylpyrazol-4-yl, 2-(1,1-dioxothiomorpholin-4-yl)pyridin-4-yl, 2-(1-methylpiperidin-3-yloxy)pyridin-4-yl, 2-(1-methylpiperidin-4-yloxy)pyridin-4-yl, 2-(1-methylpyrrolidin-3-yloxy)pyridin-4-yl, 2-(2-methoxyethan-1-yloxy)pyridin-4-yl, 2-(3-oxopiperazin-l-yl)pyridin-4-yl, 2-(4-acetylpiperazin-1-yl)pyridin-4-yl, 2-(4-methylpiperazin-l-yl)pyridin-4-yl, 2-(4-methylsulfonylpiperazin-1-yl)pyridin-4-yl, 2-(morpholin-4-yl)pyridin-4-yl, 2-(oxetan-3-yloxy)pyridin-4-yl, 2-(piperidin-3-yloxy)pyridin-4-yl, 2-(piperidin-4-yloxy)pyridin-4-yl, 2-(pyrrolidin-3-yloxy)pyridin-4-yl, 2,6-dimethylpyridin-4-yl, 2-isopropoxypyridin-4-yl, 2-isopropylaminopyridin-4-yl, 2-methylaminocarbonyl-6-methylpyridin-4-yl, 2-methylaminocarbonylpyridin-4-yl, 2-methylaminopyridin-4-yl, 2-methylpyridin-4-yl, 2-morpholin-4-ylpyridin-4-yl, 2-pyrrolidin-1-ylpyridin-4-yl, 4-(1,1-dioxothiomorpholin-4-ylcarbonyl)cyclohexyl, 4-(2-oxa-6-azaspiro[3.3]heptan-6-ylcarbonyl)cyclohexyl, 4-(4,4-difluoropiperidin-1-ylcarbonyl)cyclohexyl, 4-(4-methylpiperazin-1-yl)carbonylcyclohexyl, 4-(morpholin-4-ylcarbonyl)cyclohexyl, 4-hydroxycarbonylcyclohexyl, 4-methylpyridin-3-yl, 5-(4-methylpiperazin-1-ylcarbonyl)pyridin-3-yl, 5-(morpholin-4-ylmethyl)pyridin-3-yl, 5-(pyrrolidin -1-ylcarbonyl)pyridin-3-yl, 5-(S-imino(methyl)sulfinyl)pyridin-3-yl, 5-aminocarbonylpyridin-3-yl, 5-cyanopyridin-3-yl, 5-dimethylaminocarbonylpyridin-3-yl, 5-fluoropyridin-3-yl, 5-hydroxycarbonylpyridin-3-yl, 5-methylaminocarbonylpyridin-3-yl, 5-methylaminosulfonylpyridin-3-yl, 5-methylpyridin-3-yl, 5-methylsulfonylpyridin-3-yl, 6-(1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-6-yl)pyridin-4-yl, 6-(1-methylpiperazin-4-yl)pyridin-3-yl, 6-(2-(2-hydroxypropan-2yl)morpholin-4-yl)pyridin-4-yl, 6-(2,5-dioxa-8-azaspiro[3.5]nonan-8-yl)pyridin-4-yl, 6-(2-hydroxypropan-2-yl)pyridin-4-yl, 6-(2-methyl -4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-5-yl)pyridin-4-yl, 6-(2-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-5-yl)pyridin-4-yl, 6-(2-methyl-5,6-dihydro-4H-pyrrolo[3,4-d]thiazol-5-yl)pyridin-4-yl, 6-(2-oxa-6-azaspiro[3.3]heptan-6-yl)pyridin-4-yl, 6-(2-oxa-6-azaspiro[3.4]octan-6-yl)pyridin-4-yl, 6-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-4-yl, 6-(2-oxo -oxazol-3-yl)pyridin-4-yl, 6-(3-methyl-3-hydroxyazetidin-1-yl)pyridin-4-yl, 6-(3-methyl-3-hydroxypyrrolidin-1-yl)pyridin-4-yl, 6-(3-oxa-7-azaspiro[3.5]nonan-7-yl)pyridin-4-yl, 6-(3-oxomorpholin-4-yl)pyridin-4-yl, 6-(4-(cyclopropylsulfonyl)piperazin-1-yl)pyridin-4-yl, 6-(4-(N-isopropyl-N-ethylaminocarbonyl)piperazin-1-yl)pyridin-4-yl, 6-(4-(oxetan-3-yl)piperazin-1-yl)pyridin-4-yl, 6-(4-(oxetan-3-ylcarbonyl)piperazin-1-yl)pyridin-4-yl, 6-(4-(oxetan-3-ylmethyl)piperazin-1-yl)pyridin-4-yl, 6-(4-(oxetan-3-yloxycarbonyl)piperazin-1-yl)pyridin-4-yl, 6-(4-methoxycarbonylpiperazin-1-yl)pyridin-4-yl, 6-(4-methyl-4-hydroxypiperidin-1-yl)pyridin -4-yl, 6-(4-methylpiperazin-1-ylcarbonyl)pyridin-3-yl, 6-(4-methylpiperazin-1-ylmethyl)pyridin -4-yl, 6-(4-trifluoromethylsulfonylpiperazin-1-yl)pyridin-4-yl, 6-(8-oxa-3-azabicyclo [3.2. ]octan- 3-yl)pyridin-4-yl, 6-(hexahydro-1H-furo[3,4-c]pyrrol-5-yl)pyridin-4-yl, 6-(isopropylamino -carbonyl)pyridin-3-yl, 6-(methylaminocarbonyl)pyridin-3-yl, 6-(morpholin-4-yl)pyridin-4-yl, 6-(morpholin- 4 -ylcarbonyl)pyridin-3-yl, 6-(morpholin-4-ylmethyl)pyridin-3-yl, 6-(oxetan-3-yl)pyridin-4-yl, 6-(piperazin-l-yl)pyridin-4-yl, 6-(pyridin-3-yloxy)pyridin-4-yl, 6-(S -imino(methyl)sulfinyl)pyridin-4-yl, 6-(S-methyl-S-iminosulfinyl)pyridin-3-yl, 6-(tetrahydro -pyran-3-ylamino)pyridin-4-yl, 6-(tetrahydropyran-4-ylamino)pyridin-4-yl, 6-fluoropyridin-4-yl, 6-methylaminosulfonylpyridin-3-yl, 6-methylpyridin-3-yl, 6-methylpyridin-4-yl, or 6-methylsulfonylpyridin-3-yl.
4. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R 2 is 4-hydroxycyclohexyl optionally substituted with one to three substituents selected from -CH 3 and fluoro, or is 4,5,6,7-tetrahydro-1H-indazol-5-yl.
5. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein R 3 is isopropyl, n-butanyl, heptan-2-yl, propan-2-yl, 3-methoxypropan-2-yl, 3,3-(difluoromethoxy)propan-2-yl, 3,3-difluoropropan-2-yl, 3-cyclopropylpropan-2-yl, 4,4,4-trifluorobutan-2-yl, 4-fluorobutan-2-yl, 4,4-difluorobutan-2-yl, 2-methoxyethan-l-yl, 2-cyclopropanylethan-1-yl, or 3,3,3-trifluoropropan-1-yl.
6. The compound of claim 1 , having structural Formula IV:
or structural Formula V:
or a pharmaceutically acceptable salt thereof, wherein:
R 8 is-(C 0 -C 4 alkylene)-S(O) 2 -(C 1 -C 3 alkyl), -C(O)-NH-(C 1 -C 4 alkyl), -C 1 -C 4 alkyl optionally substituted with one or more of halo, hydroxy and cyano, -NH-(C 1 -C 4 alkyl), -O-(C 1 -C 3 alkylene)-O-(C 1 -C 4 alkyl), -O-(C 1 -C 4 alkyl), -S(O)(═NH)-(C 1 -C 4 alkyl), -S(O) 2 -NH-(C 1 -C 4 alkyl) , -(C 0 -C 3 alkylene)-C(O)-heterocyclyl, -(C 0 -C 3 alkylene)-NH-heterocyclyl, -(C 0 -C 4 alkylene)-heterocyclyl, -O-heteroaryl, or -O-heterocyclyl, wherein any heterocyclyl, or heteroaryl portion of R 8 is optionally further substituted;
R 7 is -O-C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or -O-C 1 -C 3 haloalkyl;
R 12 is hydrogen or C 1 -C 4 alkyl; and
each is R 13a and R 13b is independently selected from hydrogen and fluoro.
7. The compound of claim 6 or the pharmaceutically acceptable salt thereof, wherein R 8 is -CH 3 , -C(O)NHCH 3 , -C(O)NHCH(CH 3 ) 2 , -NHCH(CH 3 ) 2 , -NHCH 3 , -S(═O)(═NH)-CH 3 , -S(═O) 2 -CH 3 , -S(═O) 2 -NH-CH 3 , 1,1-dioxothiomorpholin-4-yl, 1-methyl -1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl, 1-methylpiperidin-3-yloxy, 1-methylpiperidin-4-yloxy, 1-methylpyrrolidin-3-yloxy, 1-oxa-7-azospiro[3.5]nonan-7-yl, 2-(2-hydroxypropan-2-yl)morpholin-4-yl, 2,5-dioxa-8-azospiro[3.5]nonan-8-yl, 2-methoxyethan-1-yloxy, 2-methyl-4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-5-yl, 2-methyl-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl, 2-oxa-6-azospiro[3.3]heptan-6-yl, 2-oxa-6-azospiro[3.5]octan-6-yl, 2-oxa-7-azospiro[3.5]nonan-7-yl, 2-oxo-oxazolidin-3-yl, 3-oxomorpholin-4-yl, 3-oxopiperazin-l-yl, 4-(N-ethyl-N-isopropylaminocarbonyl)piperazin-1-yl, 4-(oxetan-3-yl)piperazin-1-yl, 4-(oxetan-3-ylmethyl)piperazin-1-yl, 4-acetylpiperazin-1-yl, 4-cyclopropylsulfonylpiperazin-1-yl, 4-methoxycarbonylpiperazin-1-yl, 4-methylpiperazin-1-yl, 4-methylpiperazin-1-ylmethyl, 4-sulfonylmethylpiperazin-1-yl, 4-trifluoromethylsulfonylpiperazin-1-yl, 8-oxa-3-azabicyclo[3.2.1]octan-3-yl, isopropyloxy, morpholin-4-carbonyl, morpholin-4-yl, morpholin-4-ylmethyl, oxetan-3-yl, oxetan-3-yloxy, piperazin-1-yl, piperidin-3-yloxy, piperidin-4-yloxy, pyridin-3-yloxy, pyrrolidin-1-yl, pyrrolidin-3-yloxy, tetrahydro-1H-furo[3,4-c]pyrrol-5-yl, tetrahydrofuran-3-ylamino, or tetrahydropyran-4-yl.
8. The compound of claim 6 or the pharmaceutically acceptable salt thereof, wherein R 8 is morpholin-4-yl, -S(═O)(═NH)-CH 3 , or -S(═O) 2 -CH 3 .
9. The compound of claim 6 or the pharmaceutically acceptable salt thereof, wherein R 7 is -OCH 3 , -CF 3 , or -OCHF 2 .
10. The compound of claim 6 or the pharmaceutically acceptable salt thereof, wherein R 12 is hydrogen or -CH 3 .
11. The compound of claim 10 , wherein each of R 12 , R 13a and R 13b is hydrogen and the compound has structural formula IVa
structural formula Va
or is a pharmaceutically acceptable salt of either of the foregoing.
12. The compound of claim 1 , having structural Formula VI:
or a pharmaceutically acceptable salt thereof, wherein:
R 7 is -O-C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or -O-C 1 -C 3 haloalkyl;
each of R 9a and R 9b are -CH 3 , or R 9a and R 9b are taken together with the carbon atom to which they are bound to form cyclopropyl;
R 9 is C 1 -C 3 alkyl, C 1 -C 3 hydroxyalkyl, -COOH, -C(O)NH-C 1 -C 4 alkyl, -CH 2 - heterocyclyl, -C(═O)-heterocyclyl or a 5-membered heteroaryl, wherein the heterocyclyl or heteroaryl portion of R 9 is optionally substituted with up to two substituents independently selected from oxo, cyclopropyl, -OH, -CN, -C 1 -C 3 alkyl, and -C 1 -C 3 hydroxyalkyl; and
R 12 is hydrogen or C 1 -C 4 alkyl; and
each of R 13a and R 13b is independently selected from hydrogen and fluoro.
13. The compound of claim 12 or the pharmaceutically acceptable salt thereof, wherein R 7 is -OCH 3 , -CF 3 , or -OCHF 2 .
14. The compound of claim 12 or the pharmaceutically acceptable salt thereof, wherein R 9 is -CH 3 , -CH 2 OH, -COOH, -C(O)NHCH 3 , -C(O)NHCH(CH 3 ) 2 , 1,1-dioxothiomorpholin-4-ylcarbonyl, 2-(2-hydroxypropan-2-yl)morpholin-4-ylcarbonyl, 2,2-dimethylmorpholin-4-ylcarbonyl, 2,5-dioxa-8-azaspiro[3.5]nonan-8-ylcarbonyl, 2,6-dimethylmorpholin-4-ylcarbonyl, 2-oxa-6-azaspiro[3.3]heptan-6-ylcarbonyl, 2-oxa-6-azaspiro[3.4]octan-6-ylcarbonyl, 3-hydroxpyrrolidin-l-ylcarbonyl, 4-cyano-4-methylpiperidin-1-ylcarbonyl, 4-hydroxy-4-methylpiperidin-1-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, 5-cyclopropyl-1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 8-oxa-3-azabicyclo[3.2.1]octan-3-ylcarbonyl, azetidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, morpholin-4-ylmethyl, pyrrolidin-1-ylcarbonyl, or tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-ylcarbonyl.
15. The compound of claim 14 or the pharmaceutically acceptable salt thereof, wherein R 9 is morpholin-4-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, 2-oxa-6-azaspiro [3.3]heptan-6-ylcarbonyl, 3-methyl-3-hydroxypyrrolidin-1-ylcarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl, or 5-methyl-1,3,4-thiadiazol-2-yl.
16. The compound of claim 12 or the pharmaceutically acceptable salt thereof, wherein R 12 is hydrogen or -CH 3 .
17. The compound of claim 16 , wherein each of R 12 , R 13a and R 13b is hydrogen and the compound has structural formula VIa:
or the pharmaceutically acceptable salt thereof.
18. The compound of claim 1 having structural Formula VII:
or a pharmaceutically acceptable salt thereof, wherein:
R 7a is C 1 -C 4 alkyl, -O-C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or -O-C 1 -C 3 haloalkyl;
R 9 is -COOH, -C(═O)-heterocyclyl or a 5-membered heteroaryl, wherein R 9 is optionally substituted with up to two substituents independently selected from oxo, -OH and -C 1 -C 3 alkyl; and
R 12 is hydrogen, or C 1 -C 4 alkyl; and
each of R 13a and R 13b is independently selected from hydrogen and fluoro.
19. The compound of claim 18 or the pharmaceutically acceptable salt thereof, wherein R 7 a is -(CH 2 ) 3 CH 3 , -OCH 3 , -CF 3 , or -OCHF 2 .
20. The compound of claim 19 , wherein R 7a is -(CH 2 ) 3 CH 3 , -OCH 3 , or -CF 3 .
21. The compound of claim 17 or the pharmaceutically acceptable salt thereof, wherein R 9 is -COOH, morpholin-4-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, 2-oxa-6-azaspiro[3.3]heptan-6-ylcarbonyl, 3-methyl-3-hydroxypyrrolidin-1-ylcarbonyl, 5-methyl-1,3,4-oxadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, or 1,1-dioxothiomorpholin-4-ylcarbonyl.
22. The compound of claim 21 or the pharmaceutically acceptable salt thereof, wherein R 9 is morpholin-4-ylcarbonyl.
23. The compound of claim 17 or the pharmaceutically acceptable salt thereof, wherein R 12 is hydrogen or -CH 3 .
24. The compound of claim 18 or the pharmaceutically acceptable salt thereof, wherein each of R 12 , R 13a and R 13b is hydrogen and the compound has structural formula VIIa:
25. A compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt of any of foregoing compounds.
26. The compound of claim 1 or the pharmaceutically acceptable salt thereof, wherein the compound demonstrates a K i against MERTK at least two times lower than its K i against FLT3.
27. A pharmaceutical composition comprising the compound of claim 1 or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
28. A pharmaceutical composition comprising the compound of claim 25 or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.